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Radiation dosimetry and first therapy results with a (124)I/ (131)I-labeled small molecule (MIP-1095) targeting PSMA
Christian M Zechmann1, Ali Afshar-Oromieh, Tom Armor
1Department of Nuclear Medicine, University Hospital Heidelberg, Im Neuenheimer Feld 400, 69120, Heidelberg, Germany.
Introduction:
Since the prostate-specific membrane antigen (PSMA) is frequently over-expressed in prostate cancer (PCa) several PSMA-targeting molecules are under development to detect and treat metastatic castration resistant prostate cancer (mCRPC). We investigated the tissue kinetics of a small molecule inhibitor of PSMA ((S)-2-(3-((S)-1-carboxy-5-(3-(4-[(124)I]iodophenyl)ureido)pentyl)ureido)pentanedioicacid; MIP-1095) using PET/CT to estimate radiation dosimetry for the potential therapeutic use of (131)I-MIP-1095 in men with mCRPC. We also report preliminary safety and efficacy of the first 28 consecutive patients treated under a compassionate-use protocol with a single cycle of (131)I-MIP-1095.
Methods:
Sixteen patients with known prostate cancer underwent PET/CT imaging after i.v. administration of (124)I-MIP-1095 (mean activity: 67.4 MBq). Each patient was scanned using PET/CT up to five times at 1, 4, 24, 48 and 72 h post injection. Volumes of interest were defined for tumor lesions and normal organs at each time point followed by dose calculations using the OLINDA/EXM software. Twenty-eight men with mCRPC were treated with a single cycle of (131)I-MIP-1095 (mean activity: 4.8 GBq, range 2 to 7.2 GBq) and followed for safety and efficacy. Baseline and follow up examinations included a complete blood count, liver and kidney function tests, and measurement of serum PSA.
Results:
I-124-MIP-1095 PET/CT images showed excellent tumor uptake and moderate uptake in liver, proximal intestine and within a few hours post-injection also in the kidneys. High uptake values were observed only in salivary and lacrimal glands. Dosimetry estimates for I-131-MIP-1095 revealed that the highest absorbed doses were delivered to the salivary glands (3.8 mSv/MBq, liver (1.7 mSv/MBq) and kidneys (1.4 mSv/MBq). The absorbed dose calculated for the red marrow was 0.37 mSv/MBq. PSA values decreased by >50 % in 60.7 % of the men treated. Of men with bone pain, 84.6 % showed complete or moderate reduction in pain. Hematological toxicities were mild. Of men treated, 25 % had a transient slight to moderate dry mouth. No adverse effects on renal function were observed.
Conclusion:
Based on the biodistribution and dose calculations of the PSMA-targeted small molecule (124)I-MIP-1095 therapy with the authentic analog (131)I-MIP-1095 enables a targeted tumor therapy with unprecedented doses delivered to the tumor lesions. Involved lymph node and bone metastases were exposed to estimated absorbed doses upwards of 300 Gy.
Insights
This study shows that (131)I-MIP-1095 effectively targets prostate cancer (PCa) lesions, delivering high radiation doses for therapy. Preliminary results indicate significant PSA reduction and pain relief in metastatic castration-resistant prostate cancer (mCRPC) patients with manageable side effects.
Area of Science:
- Nuclear Medicine
- Oncology
- Radiopharmaceuticals
Background:
- Prostate-specific membrane antigen (PSMA) is over-expressed in prostate cancer (PCa), making it a target for detection and treatment.
- PSMA-targeting molecules are being developed for metastatic castration-resistant prostate cancer (mCRPC).
- MIP-1095 is a small molecule inhibitor of PSMA investigated for therapeutic use.
Purpose of the Study:
- To investigate the tissue kinetics and radiation dosimetry of (124)I-MIP-1095 in patients with PCa.
- To estimate radiation dosimetry for the therapeutic application of (131)I-MIP-1095 in men with mCRPC.
- To report preliminary safety and efficacy of (131)I-MIP-1095 therapy in mCRPC patients.
Main Methods:
- Sixteen patients with PCa underwent PET/CT imaging after (124)I-MIP-1095 administration, with scans at multiple time points.
- Volumes of interest were defined for tumor lesions and normal organs for dose calculations using OLINDA/EXM software.
- Twenty-eight men with mCRPC received a single cycle of (131)I-MIP-1095, followed by safety and efficacy assessments including blood counts, organ function tests, and PSA levels.
Main Results:
- PET/CT images showed excellent tumor uptake of (124)I-MIP-1095, with moderate uptake in liver, intestine, and kidneys, and high uptake in salivary and lacrimal glands.
- Dosimetry estimates for (131)I-MIP-1095 indicated highest absorbed doses to salivary glands (3.8 mSv/MBq), liver (1.7 mSv/MBq), and kidneys (1.4 mSv/MBq).
- PSA levels decreased by >50% in 60.7% of treated patients, with 84.6% experiencing pain reduction. Hematological toxicities were mild, and 25% reported transient dry mouth.
Conclusions:
- The PSMA-targeted small molecule (124)I-MIP-1095 enables targeted tumor therapy with (131)I-MIP-1095, delivering unprecedented doses to tumor lesions.
- Involved lymph node and bone metastases received estimated absorbed doses exceeding 300 Gy.
- Therapy with (131)I-MIP-1095 shows promise for treating mCRPC, with significant efficacy and a favorable safety profile.
